Nanozymes for Bone Regeneration: Mechanistic Insights into Immune and Metabolic Microenvironment Modulation

Nanozymes, a class of nanomaterials with intrinsic enzyme-mimetic properties, have emerged as promising therapeutic platforms for bone regeneration due to their low cost, high stability, and multifunctionality. This review provides mechanistic insights and translational perspectives on how nanozymes act as microenvironmental "remodelers" to enhance bone repair. Representative systems-including cerium oxide (CeO₂), manganese-based (Mn₃O₄/MnO₂), and Prussian blue (PBNPs)-exert therapeutic effects by scavenging ROS, promoting M2 macrophage polarization, restoring mitochondrial function, suppressing the NLRP3/NF-κB signaling axis, and clearing deleterious metabolites such as lactate. We systematically discuss immune regulation, metabolic intervention, and their synergistic crosstalk, highlighting their capacity for spatiotemporal coordination of angiogenesis and antimicrobial defense. Finally, we outline future directions, including enhancing catalytic specificity, improving in vivo stability, addressing biosafety and pharmacokinetics, developing intelligent nanozyme designs, and establishing clinically relevant evaluation models to accelerate translation into effective bone therapies.